Eosinophil-driven Corticotherapy for Patients Hospitalized for COPD Exacerbation

COPD Exacerbation Clinical Trial

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Official title:

Eosinophil-driven Corticotherapy for Patients Hospitalized for COPD Exacerbation: a Double-blind, Randomized, Controlled Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04234360
• Other study ID #: RECHMPL19_0069 UF 7771
• Secondary ID: 2019-002724-33LI
• Status: Recruiting
• Phase: Phase 3
• Start date: October 12, 2021
• Est. completion date: January 12, 2025

Study information

• Verified date: January 2024
• Source: University Hospital, Montpellier
• Contact: Arnaud BOURDIN
• Phone: 0033467336126
• Email: a-bourdin[@]chu-montpellier.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective of this study is to compare treatment failure rates between a group of eosinophilic (eosinophilia > 2% on day 1 of hospitalization) patients hospitalised for a COPD exacerbation treated via corticotherapy versus a similar group treated via placebo.

Secondarily, treatment failure rates will also be compared between a group of non-eosinophilic patients hospitalised for a COPD exacerbation treated via corticotherapy versus a similar group treated via placebo. Study arms will also be compared for additional aspects of efficacy and safety:

• speed of recovery during the initial hospitalization;

• corticosteroid side effects / induced comorbidities;

• changes in symptoms and episodes of exacerbation;

• pulmonary function, oxygen use and ventilation;

• patient trajectories and resource use (e.g. survival, consults, episodes of hospitalization, medications);

• drug consumption (especially as relates to COPD management, exacerbations and induced comorbidities);

• health status, quality of life, activity/disability;

• patient safety / adverse events in general.

Eosinophilia thresholds optimizing the prediction of corticosteroid response and COPD outcomes will be re-evaluated. The relationships between corticosteroid response and key biomarkers (e.g. infectious groups) will be thoroughly explored, including within eosinophil strata. Potential gender subgroups differences will also be evaluated.

Finally, in prevision of further exploratory studies, a biological collection and an imaging library will be created in association with this protocol. The biological collection will be used to explore the genetic basis and physiology linked with treatment response, gender and patient trajectories. The image library will be used as a platform for the exploration of new imaging markers developed, for example, via machine learning and affiliated techniques.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 600
• Est. completion date: January 12, 2025
• Est. primary completion date: October 12, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 85 Years

Eligibility

Inclusion Criteria:

• Adult patients admitted to a participating hospital (ward, ICU or emergency services) for an acute COPD exacerbation

• For patients with known COPD: COPD defined according to GOLD 2018 criteria: (1) Post-bronchodilator FEV1/FVC < 70% of predicted values; (2) > 10 pack years smoking history

• For incident COPD cases with no spirometric history: symptoms and exposure according to GOLD 2018 report will be considered for the diagnosis, but if the spirometric diagnosis is not confirmed during follow-up, then the patient will be excluded

• Signed consent has been obtained, or the appropriate emergency procedure (under French law) allows enrolment

• Subjects must be covered by public health insurance

• Patient available for 3 months of follow-up. Subjects must be able to attend all scheduled visits and to comply with all trial procedures.

Exclusion Criteria:

• Subject unable to read or write; language barrier

• Subject who is in a dependency or employment with the sponsor or investigator

• Pregnancy or lactation

• Patients who are prisoners or under other forms of judicial protection

• Patients under any kind of guardianship

• The patient has already participated in the present protocol

• The patient is participating in another interventional study or has done so in the past 3 months

• The patient is in an exclusion period determined by a previous study

• The patient has been taking long-term systemic corticosteroids for longer than 1 month prior to inclusion

• The patient has already received > 1 mg/kg of systemic corticotherapy in the past 48h

• Intubated-ventilated patient

• Administration of oral experimental drug is impossible

• Cancer within the last 12 months

• Current diagnosis of Asthma

• T2-inflammation targeting biologics (Benralizumab, reslizumab, mepolizumab, dupilumab) treatment

• Admitted for any other reason including, but not limited to, pulmonary embolism, pneumothorax, heart failure

• Known allergy to corticosteroids

• Consideration of a potential negative drug interaction with corticosteroids (at the investigator's discretion)

• White blood cell formula already performed and distributed to implicated teams

• Directives for limitation-of-care ("LATA" in French) already established

• SARS-Cov2 positive test carry out during the COPD exacerbation

Related Conditions & MeSH terms

• COPD Exacerbation
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• 5 days of systemic corticotherapy (prednisone)
Patients randomized to this arm will receive 40 mg prednisone per os per day for 5 days. Other aspects of standard, recommended care (e.g. antibiotherapy) are respected.
• 5 days of placebo
Patients randomized to this arm will receive an appropriate placebo per os for 5 days. Other aspects of standard, recommended care (e.g. antibiotherapy) are respected.

Locations

Country	Name	City	State
France	CHU Amiens	Amiens
France	CHU Brest - Hôpital Caval Blanche	Brest
France	Clinique du Parc	Castelnau-le-Lez
France	Centre hospitalier intercommunal de Créteil	Créteil
France	CH Libourne	Libourne
France	CHRU Lille	Lille
France	Hospice Civils de Lyon	Lyon
France	APHM - Hôpital Nord	Marseille
France	CHU Montpellier	Montpellier
France	CHU Nancy	Nancy
France	CHU Nîmes	Nîmes
France	APHP - Hôpital BICHAT	Paris
France	APHP - Hôpital Cochin	Paris
France	APHP - Hopital Européen Georges Pompidou	Paris
France	APHP - Hôpital Universitaire Pitié-Salpétrière	Paris
France	APHP - Hôpital Universitaire Pitié-Salpétrière	Paris
France	CHU Bordeaux - Hôpital Haut Lévêque	Pessac
France	CHU Reims	Reims
France	CH Roubaix	Roubaix
France	CHRU Strasbourg	Strasbourg
France	Hôpital Larrey CHU Toulouse	Toulouse
France	Hôpital Nord Franche-Comté	Trévenans

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Montpellier

Country where clinical trial is conducted

France, 

References & Publications (1)

Suehs CM, Zysman M, Chenivesse C, Burgel PR, Couturaud F, Deslee G, Berger P, Raherison C, Devouassoux G, Brousse C, Roche N, Molimard M, Chinet T, Devillier P, Chanez P, Kessler R, Didier A, Martinat Y, Le Rouzic O, Bourdin A. Prioritising outcomes for evaluating eosinophil-guided corticosteroid therapy among patients with acute COPD exacerbations requiring hospitalisation: a Delphi consensus study. BMJ Open. 2020 Jul 1;10(7):e035811. doi: 10.1136/bmjopen-2019-035811. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Blood differential		Baseline (day 0)
Other	Blood differential		day 2
Other	Blood differential		On hospital discharge (expected maximum of 28 days)
Other	Blood differential		1 month
Other	Blood differential		3 months
Other	C reactive protein		Baseline (day 0)
Other	C reactive protein		On hospital discharge (expected maximum of 28 days)
Other	Sputum bacteriological analysis (or nasal swab if no sputum)		Baseline (day 0)
Other	Nasal swab virology		Baseline (day 0)
Other	Computed tomography scan of lungs: presence/absence of consolidation		Baseline (day 0); optional
Other	Computed tomography scan of lungs: presence/absence of consolidation		3 months; optional
Other	Computed tomography scan of lungs: % emphysema		Baseline (day 0); optional
Other	Computed tomography scan of lungs: % emphysema		3 months; optional
Primary	Treatment failure	Treatment failure for the primary outcome is defined according to Niewoehner et al. (1999) as death from any cause or need for intubation and mechanical ventilation, readmission due to COPD, or intensification of pharmacologic therapy (defined as the prescription of open-label systemic glucocorticoids, high-dose inhaled glucocorticoids (more than eight puffs per day of triamcinolone acetonide or its equivalent), theophylline, or any combination of these three therapies) at three months. In addition, an investigator meeting determined additional components of treatment failure that should be added to Niewoehner's definition in order to bring it up-to-date : Initiation of non-invasive ventilation for >24h after first treatment administration; Transfer to intensive care or indication for a transfer to intensive care. Incident limitations-of-care that can affect treatment failure should also be carefully noted.	3 months
Secondary	The speed of initial recovery: Time elapsed before showing signs of improvement		During initial hospitalization (expected maximum of 28 days)
Secondary	The speed of initial recovery: Time elapsed in acidosis/hypercapnia		During initial hospitalization (expected maximum of 28 days)
Secondary	The speed of initial recovery: Time elapsed before meeting pre-defined discharge criteria	Time elapsed before meeting pre-defined discharge criteria (acidosis has normalized, symptoms have returned to manageable levels, the patient is capable of performing minimal daily activities).	During initial hospitalization (expected maximum of 28 days)
Secondary	Presence /absence of comorbidities or steroid side effects: glycemia		During initial hospitalization (expected maximum of 28 days)
Secondary	Presence /absence of comorbidities or steroid side effects: glycemia		1 month
Secondary	Presence /absence of comorbidities or steroid side effects: glycemia		3 months
Secondary	The occurrence of new or worsened diabetes/hyperglycemia		Throughout the study (3 months)
Secondary	Body mass index		Baseline (day 0)
Secondary	Body mass index		At hospital discharge (expected maximum of 28 days)
Secondary	Body mass index		1 month
Secondary	Body mass index		3 month
Secondary	Hospital anxiety and depression scale (HAD)	The HAD results in a score ranging from 0 (low anxiety or depression) to 21 (strong anxiety or depression).	baseline (day 0)
Secondary	Hospital anxiety and depression scale (HAD)	The HAD results in a score ranging from 0 (low anxiety or depression) to 21 (strong anxiety or depression).	3 months
Secondary	The occurrence of any other potentially corticosteroid-induced comorbidities throughout the study		Throughout the study; 3 months
Secondary	Episodes of pneumonia	Beginning and end dates of episodes.	Throughout the study; 3 months
Secondary	Episodes of infection	Beginning and end dates of episodes.	Throughout the study; 3 months
Secondary	Episodes of mild exacerbation.	Episodes of exacerbation will be recorded (date of start/finish for each episode) throughout the study.; Exacerbation severity is determined (GOLD 2018) as follows: mild: treated with short acting bronchodilators (SABDs) only,; moderate: treated with SABDs plus antibiotics and/or oral corticosteroids,; severe: patient required hospitalization or visits the emergency room.	Throughout the study; 3 months
Secondary	Episodes of moderate exacerbation.	Episodes of exacerbation will be recorded (date of start/finish for each episode) throughout the study.; Exacerbation severity is determined (GOLD 2018) as follows: mild: treated with short acting bronchodilators (SABDs) only,; moderate: treated with SABDs plus antibiotics and/or oral corticosteroids,; severe: patient required hospitalization or visits the emergency room.	Throughout the study; 3 months
Secondary	Episodes of severe exacerbation.	Episodes of exacerbation will be recorded (date of start/finish for each episode) throughout the study.; Exacerbation severity is determined (GOLD 2018) as follows: mild: treated with short acting bronchodilators (SABDs) only,; moderate: treated with SABDs plus antibiotics and/or oral corticosteroids,; severe: patient required hospitalization or visits the emergency room.	Throughout the study; 3 months
Secondary	Forced expiratory volume in 1 second (litres)		At hospital discharge (expected maximum of 28 days)
Secondary	Forced expiratory volume in 1 second (litres)		3 months
Secondary	Forced expiratory volume in 1 second (% predicted)		At hospital discharge (expected maximum of 28 days)
Secondary	Forced expiratory volume in 1 second (% predicted)		3 months
Secondary	Forced vital capacity (litres)		At hospital discharge (expected maximum of 28 days)
Secondary	Forced vital capacity (litres)		3 months
Secondary	Forced vital capacity (% predicted)		At hospital discharge (expected maximum of 28 days)
Secondary	Forced vital capacity (% predicted)		3 months
Secondary	Residual volume (litres)		At hospital discharge (expected maximum of 28 days)
Secondary	Residual volume (litres)		3 months
Secondary	Residual volume (% predicted)		At hospital discharge (expected maximum of 28 days)
Secondary	Residual volume (% predicted)		3 months
Secondary	Total lung capacity (litres)		At hospital discharge (expected maximum of 28 days)
Secondary	Total lung capacity (litres)		3 months
Secondary	Total lung capacity (% predicted)		At hospital discharge (expected maximum of 28 days)
Secondary	Total lung capacity (% predicted)		3 months
Secondary	Oxygen needs (litres/min) during initial hospitalisation		At hospital discharge (expected maximum of 28 days)
Secondary	Mode of pre-hospitalization living arrangements	At home, rehabilitation centre, assisted living centre, or other	Baseline (day 0)
Secondary	Hospital discharge modality	At home, rehabilitation centre, assisted living centre, or other	At hospital discharge (expected maximum of 28 days)
Secondary	Episodes of hospitalization	Episodes of hospitalization, distinguishing emergency department, intensive care, intermediate care and ward stays, will be recorded throughout the study .	Throughout the study; 3 months
Secondary	Episodes of emergency department use		Throughout the study; 3 months
Secondary	Episodes of intensive care		Throughout the study; 3 months
Secondary	Consults	The number of consults and rehabilitation/therapy sessions in relation to COPD/respiratory symptoms (or not) will be tracked.	Throughout the study; 3 months
Secondary	The cumulative days alive and event-free	The cumulative days alive and event-free (free from hospitalization, exacerbation, ventilation, oxygen use, pneumonia or infection)	Throughout the study; 3 months
Secondary	Mortality/survival		Throughout the study; 3 months
Secondary	Medications	Drug consumption episodes (including vaccines) will be recorded throughout the study and linked to COPD exacerbations, COPD maintenance therapy or corticosteroid-induced side effects as appropriate.	Throughout the study; 3 months
Secondary	VAS scale for coughing	Patient reported, separate visual analogue scales (VAS) for coughing, dyspnoea (at rest), sputum production, sleep perturbation and anxiety.; VAS scales range from 0 (absence of symptoms) to 10 (strongest possible symptoms imaginable).	Every morning during hospitalization (expected maximum of 28 days)
Secondary	VAS scale for coughing	Patient reported, separate visual analogue scales (VAS) for coughing, dyspnoea (at rest), sputum production, sleep perturbation and anxiety.; VAS scales range from 0 (absence of symptoms) to 10 (strongest possible symptoms imaginable).	1 month
Secondary	VAS scale for coughing	Patient reported, separate visual analogue scales (VAS) for coughing, dyspnoea (at rest), sputum production, sleep perturbation and anxiety.; VAS scales range from 0 (absence of symptoms) to 10 (strongest possible symptoms imaginable).	3 months
Secondary	VAS scale for dyspnoea	Patient reported, separate visual analogue scales (VAS) for coughing, dyspnoea (at rest), sputum production, sleep perturbation and anxiety.; VAS scales range from 0 (absence of symptoms) to 10 (strongest possible symptoms imaginable).	Every morning during hospitalization (expected maximum of 28 days)
Secondary	VAS scale for dyspnoea	Patient reported, separate visual analogue scales (VAS) for coughing, dyspnoea (at rest), sputum production, sleep perturbation and anxiety.; VAS scales range from 0 (absence of symptoms) to 10 (strongest possible symptoms imaginable).	1 month
Secondary	VAS scale for dyspnoea	Patient reported, separate visual analogue scales (VAS) for coughing, dyspnoea (at rest), sputum production, sleep perturbation and anxiety.; VAS scales range from 0 (absence of symptoms) to 10 (strongest possible symptoms imaginable).	3 months
Secondary	VAS scale for sputum production	Patient reported, separate visual analogue scales (VAS) for coughing, dyspnoea (at rest), sputum production, sleep perturbation and anxiety.; VAS scales range from 0 (absence of symptoms) to 10 (strongest possible symptoms imaginable).	Every morning during hospitalization (expected maximum of 28 days)
Secondary	VAS scale for sputum production	Patient reported, separate visual analogue scales (VAS) for coughing, dyspnoea (at rest), sputum production, sleep perturbation and anxiety.; VAS scales range from 0 (absence of symptoms) to 10 (strongest possible symptoms imaginable).	1 month
Secondary	VAS scale for sputum production	Patient reported, separate visual analogue scales (VAS) for coughing, dyspnoea (at rest), sputum production, sleep perturbation and anxiety.; VAS scales range from 0 (absence of symptoms) to 10 (strongest possible symptoms imaginable).	3 months
Secondary	VAS scale for sleep perturbation	Patient reported, separate visual analogue scales (VAS) for coughing, dyspnoea (at rest), sputum production, sleep perturbation and anxiety.; VAS scales range from 0 (absence of symptoms) to 10 (strongest possible symptoms imaginable).	Every morning during hospitalization (expected maximum of 28 days)
Secondary	VAS scale for sleep perturbation	Patient reported, separate visual analogue scales (VAS) for coughing, dyspnoea (at rest), sputum production, sleep perturbation and anxiety.; VAS scales range from 0 (absence of symptoms) to 10 (strongest possible symptoms imaginable).	1 month
Secondary	VAS scale for sleep perturbation	Patient reported, separate visual analogue scales (VAS) for coughing, dyspnoea (at rest), sputum production, sleep perturbation and anxiety.; VAS scales range from 0 (absence of symptoms) to 10 (strongest possible symptoms imaginable).	3 months
Secondary	VAS scale for anxiety	Patient reported, separate visual analogue scales (VAS) for coughing, dyspnoea (at rest), sputum production, sleep perturbation and anxiety.; VAS scales range from 0 (absence of symptoms) to 10 (strongest possible symptoms imaginable).	Every morning during hospitalization (expected maximum of 28 days)
Secondary	VAS scale for anxiety	Patient reported, separate visual analogue scales (VAS) for coughing, dyspnoea (at rest), sputum production, sleep perturbation and anxiety.; VAS scales range from 0 (absence of symptoms) to 10 (strongest possible symptoms imaginable).	1 month
Secondary	VAS scale for anxiety	Patient reported, separate visual analogue scales (VAS) for coughing, dyspnoea (at rest), sputum production, sleep perturbation and anxiety.; VAS scales range from 0 (absence of symptoms) to 10 (strongest possible symptoms imaginable).	3 months
Secondary	The Breathlessness, Cough and Sputum Scale	Symptoms are evaluated on a 5-point Likert-type scale ranging from 0 to 4, with higher scores indicating more severe symptoms.	Baseline (day 0)
Secondary	The Breathlessness, Cough and Sputum Scale	Symptoms are evaluated on a 5-point Likert-type scale ranging from 0 to 4, with higher scores indicating more severe symptoms.	On hospital discharge (expected maximum of 28 days)
Secondary	The Breathlessness, Cough and Sputum Scale	Symptoms are evaluated on a 5-point Likert-type scale ranging from 0 to 4, with higher scores indicating more severe symptoms.	1 month
Secondary	The Breathlessness, Cough and Sputum Scale	Symptoms are evaluated on a 5-point Likert-type scale ranging from 0 to 4, with higher scores indicating more severe symptoms.	3 months
Secondary	The modified medical research council (mMRC) dyspnoea scale	Scores range from 0 (none) to 4 (very severe).	Baseline (day 0)
Secondary	The modified medical research council (mMRC) dyspnoea scale	Scores range from 0 (none) to 4 (very severe).	3 months
Secondary	The COPD assessment test	Scores range from 0-40 with higher scores indicative of greater COPD impact on health status.	Baseline (day 0)
Secondary	The COPD assessment test	Scores range from 0-40 with higher scores indicative of greater COPD impact on health status.	1 month
Secondary	The COPD assessment test	Scores range from 0-40 with higher scores indicative of greater COPD impact on health status.	3 months
Secondary	The Euroqol (EQ-5D-5L) questionnaire	The descriptive system has five dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each described by five levels of intensity ("no problems", "slight problems", "moderate problems", "severe problems" and "extreme problems or complete inability"). This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state.	Baseline (day 0)
Secondary	The Euroqol (EQ-5D-5L) questionnaire	The descriptive system has five dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each described by five levels of intensity ("no problems", "slight problems", "moderate problems", "severe problems" and "extreme problems or complete inability"). This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state.	1 month
Secondary	The Euroqol (EQ-5D-5L) questionnaire	The descriptive system has five dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each described by five levels of intensity ("no problems", "slight problems", "moderate problems", "severe problems" and "extreme problems or complete inability"). This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state.	3 months
Secondary	The St George Respiratory Questionnaire	Scores range from 0 to 100, with higher scores indicating more limitations.	3 months
Secondary	Six minute walking tests		1 month (optional)
Secondary	Six minute walking tests		3 months
Secondary	The DIRECT questionnaire	DIRECT: Disability related to Chronic Obstructive Pulmonary Disease (COPD) tool The DIRECT questionnaire provides a score ranging between 0 and 34, with higher values indicating higher levels of disability.	3 months

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